Primary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities

doi:10.1016/j.jpeds.2013.01.061

The Journal of Pediatrics

Volume 163, Issue 2, August 2013, Pages 383-387

https://doi.org/10.1016/j.jpeds.2013.01.061 Get rights and content

Objective

To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation.

Study design

Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed.

Results

All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community.

Conclusion

The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population.

Section snippets

Methods

Subjects from Amish communities in the midwest with neonatal respiratory distress, situs inversus totalis, chronic pneumonia, or rhinosinusitis were recruited to participate in the study, which has been described previously.¹⁷ Two probands from an Old-Order Amish community in Pennsylvania were enrolled and evaluated in a cross-sectional study supported by the Genetic Diseases of Mucociliary Clearance Consortium, and other family members with classic clinical features (Table I) were studied at

Results

All of the subjects studied had classic features, and ultrastructural examination of the cliliary axoneme revealed dynein arm defects in several affected individuals consistent with a diagnosis of PCD (Table I). Identification of multiple members from several Amish families from central Pennsylvania facilitated genome-wide homozygosity mapping, using high-density single nucleotide polymorphism arrays. These analyses localized the disease locus to chromosome 5 in a region containing a known

Discussion

PCD is a genetically heterogeneous, autosomal recessive disease resulting from impaired ciliary function. The estimated incidence is 1 in 15 000-30 000 births,23, 24 with an estimated prevalence as high as 5% in children that have recurrent respiratory infections. Investigators have identified 15 different genes that when mutated produce unambiguous clinical phenotypes and in most cases ultrastructural defects of the ciliary axoneme.4, 19, 22, 25, 26

Arising from an Anabaptist movement, the

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Cited by (14)

Deletions in DNAL1 Cause Primary Ciliary Dyskinesia Across North American Indigenous Populations
2023, Journal of Pediatrics
The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis
2022, The Lancet Respiratory Medicine
Citation Excerpt :
Recent data suggest that HYDIN variants might be present in patients with PCD in whom a previous genetic diagnosis was obscure.18 Others have described genes and variants that more commonly cause PCD in specific populations.19–24 Here, using variant frequency data from a large public sequence database along with the Hardy–Weinberg equation, we have estimated the global prevalence of PCD and identified the leading pathogenic variants and PCD-causing genes across a broad range of ethnicities, similar to approaches evaluating the prevalence of other Mendelian diseases.25–27
Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary infections. Inheritance is commonly autosomal recessive, with extensive locus and allelic heterogeneity. The prevalence is uncertain. Most genetic studies have been done in North America or Europe. The aim of the study was to estimate the worldwide prevalence and ethnic heterogeneity of PCD.
We calculated the allele frequency of disease-causing variants in 29 PCD genes associated with autosomal recessive inheritance in 182 681 unique individuals to estimate the global prevalence of PCD in seven ethnicities (African or African American, Latino, Ashkenazi Jewish, Finnish, non-Finnish European, east Asian, and south Asian). We began by aggregating variants that had been interpreted by Invitae, San Francisco, CA, USA, a genetics laboratory with PCD expertise. We then determined the allele frequency of each variant (pathogenic, likely pathogenic, or variant of uncertain significance [VUS]) in the Genome Aggregation Database (gnomAD), a publicly available next-generation sequencing database that aggregates exome and genome sequencing information from a wide variety of large-scale projects and stratifies allele counts by ethnicity. Using the Hardy–Weinberg equilibrium equation, we were able to calculate a lower-end prevalence of PCD for each ethnicity by including only pathogenic and likely pathogenic variants; and upper-end prevalence by also including VUS. This approach was similar to previous work on Li-Fraumeni (TP53 variants) prevalence. We were not diagnosing PCD, but rather estimating prevalence based on known variants.
The overall minimum global prevalence of PCD is calculated to be at least one in 7554 individuals, although this is likely to be an underestimate because some variants currently classified as VUS might be disease-causing and some pathogenic variants might not be detected by our methods. In the overall cohort, Invitae data could be included for variants without gnomAD data for a primary ethnicity. When using only gnomAD allele frequencies to calculate prevalence in individual ethnicities, the estimated prevalence of PCD was lower in each ethnicity compared with the overall cohort. This is because the overall cohort includes additional data from the Invitae database such as copy number variants and other variants not present in gnomAD. With gnomAD we found the expected PCD frequency to be higher in individuals of African ancestry than in most other populations (excluding VUS: 1 in 9906 in African or African American vs 1 in 10 388 in non-Finnish European vs 1 in 14 606 in east Asian vs 1 in 16 309 in Latino; including VUS: 1 in 106 in African or African American vs 1 in 178 in non-Finnish European vs 1 in 196 in Latino vs 1 in 188 in east Asian). In addition, we found that the top 5 genes most commonly implicated in PCD differed across ethnic ancestries and contrasted commonly published findings.
PCD appears to be more common than has been recognised, particularly in individuals of African ancestry. We identified gene distributions that differ from those in previous European and North American studies. These results could have an international impact on case identification. Our analytic approach can be expanded as more PCD loci are identified, and could be adapted to study the prevalence of other inherited diseases.
None.
Primary ciliary dyskinesia in the genomics age
2020, The Lancet Respiratory Medicine
Citation Excerpt :
A few studies have suggested an association between some genes and the severity of pulmonary disease, but the evidence remains scarce.8–11 Primary ciliary dyskinesia is estimated to affect 1 in 10 000 to 1 in 15 000 Europeans and is more common in populations with closed genetic pools;12–14 interestingly, genetic heterogeneity is seen in socially isolated consanguineous populations.15,16 Estimates of prevalence are scarce outside of Europe, but primary ciliary dyskinesia is expected to be more common in certain populations (eg, in Arab countries).17,18
Primary ciliary dyskinesia is a genetically and clinically heterogeneous syndrome. Impaired function of motile cilia causes failure of mucociliary clearance. Patients typically present with neonatal respiratory distress of unknown cause and then continue to have a daily wet cough, recurrent chest infections, perennial rhinosinusitis, otitis media with effusion, and bronchiectasis. Approximately 50% of patients have situs inversus, and infertility is common. While understanding of the underlying genetics and disease mechanisms have substantially advanced in recent years, there remains a paucity of evidence for treatment. Next-generation sequencing has increased gene discovery, and mutations in more than 40 genes have been reported to cause primary ciliary dyskinesia, with many other genes likely to be discovered. Increased knowledge of cilia genes is challenging perceptions of the clinical phenotype, as some genes reported in the last 5 years are associated with mild respiratory disease. Developments in genomics and molecular medicine are rapidly improving diagnosis, and a genetic cause can be identified in approximately 70% of patients known to have primary ciliary dyskinesia. Groups are now investigating novel and personalised treatments, although gene therapies are unlikely to be available in the near future.
Genetics and biology of primary ciliary dyskinesia
2016, Paediatric Respiratory Reviews
Citation Excerpt :
High throughput sequencing has provided us with novel gene mutations and many variants, raising new questions related to the meaning of sequence variants and null mutations in one or two different alleles that are linked to cilia function. Like many inheritable diseases, the genetic load increases with consanguinity, explaining the higher frequency of identified cases in closed populations [78]. However, it is curious that mutations leading to PCD persist in these families despite their association with male and possibly female infertility.
Ciliopathies are a growing class of disorders caused by abnormal ciliary axonemal structure and function. Our understanding of the complex genetic and functional phenotypes of these conditions has rapidly progressed. Primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. However, unlike many Mendelian genetic disorders, PCD is not caused by mutations in a single gene or locus, but rather, autosomal recessive mutation in one of many genes that lead to a similar phenotype. The first reported PCD mutations, more than a decade ago, identified genes encoding known structural components of the ciliary axoneme. In recent years, mutations in genes encoding novel cytoplasmic and regulatory proteins have been discovered. These findings have provided new insights into the functions of the motile cilia, and a better understanding of motile cilia disease. Advances in genetic tools will soon allow more precise genetic testing, mandating that clinicians must understand the genetic basis of PCD. Here, we review genetic mutations, their biological impact on cilia structure and function, and the implication of emerging genetic diagnostic tools.
Primary ciliary dyskinesia: Kartagener syndrome in a family with a novel DNAH5 gene mutation and variable phenotypes
2015, Egyptian Journal of Medical Human Genetics
Citation Excerpt :
However, no genotype phenotype correlation had been detected in a cohort of patients selected from different European and North American families, who were tested for DNAH5 gene mutation in a study by Hornef et al. [12]. On the contrary, screening of patients from Amish and Mennonite communities revealed phenotypic variability in homozygous carriers of the DNAH5 gene with 4348C>T founder mutation [13]. Therefore, we are not sure whether the phenotypic variability in our family is associated with the mutation position in the DNAH5 gene, or is simply due to the randomization of left–right asymmetry.
Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder with variable clinical manifestations, including chronic rhinosinusitis, otitis media, bronchitis, pneumonia, bronchiectasis, situs inversus totalis, reduced fertility in female patients and male infertility. The condition occurs as a result of abnormal ciliary structure and function. It is presented in early life with an estimated incidence of approximately 1/16,000–20,000. About 50% of the affected patients have situs inversus totalis leading to Kartagener syndrome (MIM: 244400). So far more than 19 causative genes have been associated with primary ciliary dyskinesia.
Here we are presenting Kartagener syndrome in a consanguineous Kuwaiti family with a novel pathogenic DNAH5 gene mutation; namely c.9864dupA; [p.Pro3289ThrfsStop52], which is predicted to result in protein truncation. In this family several homozygous individuals showed variable disease manifestations.
Molecular test helped in confirmation of the clinical diagnosis and in providing better management of the affected family members, which in turn could significantly improve overall quality of their life. Consequently, preimplantation genetic diagnosis, which is the most acceptable procedure in the Islamic countries, was offered to the heterozygous-carrier couple in order to prevent recurrence of the disease in their future generations.
Progress in diagnosis of primary ciliary dyskinesia
2022, Journal of Paediatrics and Child Health

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: Supported by the Children's Discovery Institute (to T.F.) and the National Institutes of Health (NIH; R21 HL082657 [to T.F.], R01 HL071798 [to M.K. and M.Z.], and U54 HL096458 [to T.F., J.C., M.L., M.K., and M.Z.]). The last grant supports Genetic Disorders of Mucociliary Clearance Consortium (part of NIH Rare Diseases Clinical Research Network), which receives programmatic support from the National Heart, Lung, and Blood Institute and the NIH Office of Rare Diseases Research. The views expressed do not necessarily reflect the official policies of the Department of Health and Human Services; mention of trade names, commercial practices, or organizations does not imply endorsement by the US government. The authors declare no conflicts of interest.

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Original ArticlePrimary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities

Objective

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

Genet Med

J Pediatr

Cell

Am J Hum Genet

Am J Hum Genet

J Pediatr

Am J Hum Genet

Chest

Am J Hum Genet

A human syndrome caused by immotile cilia

Science

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

Mucus clearance as a primary innate defense mechanism for mammalian airways

J Clin Invest

Cilia and models for studying structure and function

Proc Am Thorac Soc

Original Article
Primary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities